Title: HMGB1 and gender difference in pulmonary arterial hypertension Abstract: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary vascular resistance (PVR) and right ventricle (RV) hypertrophy. Despite recent progress, there is still inadequate treatment for this disease, with medial survival for the patients with Functional Class III and IV as low as 2.5 years and 6 months. There is a well-established sexual dimorphism in regard to PAH, especially idiopathic PAH, with females generally being associated with higher susceptibility to PAH, while males possessing lower survival rate and predisposition to develop RV failure. Our recently published research highlights two distinct gender-associated phenotypes of PAH: an excessive level of pulmonary vascular remodeling associated with the female gender, and an inflammation of pulmonary vascular wall and RV fibrosis in males. The pro-inflammatory signaling has been inextricably linked to initiation and progression of PAH. High mobility group box 1 (HMGB1) is a nuclear factor released during cell death that stimulates immune cell activation via p PRR), including toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproducts (RAGE). TLR4 activation increases pro-inflammatory immune cell activation. In contrast, RAGE, while involved in inflammation, can limit an immune response and activate pro-surviving process. A recent publication reveals that males and females are prone to different types of the cell death in response to initial damage, with male cells more likely to die by necrosis, and females ? by apoptosis. As HMGB1 needs to be in a reduced state to bind to TLR4, we hypothesize that the reduced environment created by necrotic cell death promotes HMGB1 mediated TLR4 activation and inflammation in males, while in females, apoptotic cells release HMGB1 in oxidized state, leading to activation of RAGE and proliferative response. e have designed peptides to selectively inhibit necrosis-mediated TLR4 activation or the apoptosis-mediated RAGE activation by prevention of their interaction with HMGB1. We will further investigate the therapeutic potential of these peptides by testing them in a rodent model of PAH for the ability to inhibit TLR4 or RAGE and, thus, evaluate the particular contribution of these pathways in PAH of either sex. attern recognition receptors ( W